© 2000 by Oxford University Press
Journal of the National Cancer Institute, Vol. 92, No. 14, 1126-1135,
July 19, 2000
© 2000 Oxford University Press
REVIEW |
Genetic and Hormonal Risk Factors in Breast Cancer
Affiliation of authors: Department of Medicine, Division of Hematology and Oncology, University of Pennsylvania, Philadelphia.
Correspondence to: Barbara L. Weber, M.D., Department of Medicine, Division of Hematology and Oncology, University of Pennsylvania, Rm. 316A, BRBII/III, 421, Curie Blvd., Philadelphia, PA 19104 (e-mail: weberb{at}mail.med.upenn.edu)
 |
ABSTRACT |
|---|
 Top Abstract IntroductionRisk Factors and Breast...Breast Cancer Susceptibility...Other Susceptibility AllelesLow-Penetrance Breast Cancer...ConclusionReferences |
|---|
Breast cancer poses a serious public health problem, and it is hoped that identification of genetic and environmental factors that contribute to the development of breast cancer will enhance prevention efforts. Two breast cancer susceptibility genes (BRCA1 and BRCA2) have been identified, and germline mutations in these genes are thought to account for between 5% and 10% of all breast cancer cases. Current findings suggest that mutations in other highly penetrant genes may play an important role in breast cancer susceptibility, and studies aimed at the isolation of these genes are under way. In addition, common variants in a number of gene classes are thought to act as low-penetrance susceptibility alleles, and efforts to identify and characterize these variants are under way. This review discusses the genetic components of susceptibility to breast cancer from the standpoint of both human genetics and rat models.
|
INTRODUCTION |
|---|
|
TopAbstractIntroductionRisk Factors and Breast...Breast Cancer Susceptibility...Other Susceptibility AllelesLow-Penetrance Breast Cancer...ConclusionReferences |
|---|
Breast cancer is a complex, multifactorial disease where there is a strong interplay between genetic and environmental factors. At present, approximately 180 000 women are diagnosed with breast cancer each year in the United States (1). Clearly, this is a serious public health issue, and efforts to understand the etiology of the disease are essential. To this end, tremendous strides have been made in the identification of factors that contribute to the development of breast cancer. As a result of this ongoing work, two major breast cancer susceptibility genes have been isolated, regions of the human genome that harbor as yet unidentified breast cancer-related genes have been identified, and a number of somatically altered genes have been characterized.
Although nongenetic factors also clearly play a role in the familial clustering of breast cancer, 5%–10% of all breast cancers can be explained by the inheritance of mutations in one of the two major breast cancer susceptibility genes (2). However, a great deal remains to be understood regarding the number of heritable genetic factors involved in breast cancer, the function of such genes, and the prevalence of breast cancer-associated mutations. In addition, very little is known about the interaction of genes with environmental influences and their relationship to breast cancer. This review provides 1) an overview of the risk factors associated with breast cancer development, 2) a description of the two major susceptibility genes (i.e., BRCA1 and BRCA2), 3) a short description of rare susceptibility alleles, and 4) a summary of potential low-penetrance breast cancer susceptibility genes.
|
RISK FACTORS AND BREAST CANCER SUSCEPTIBILITY |
|---|
|
TopAbstractIntroductionRisk Factors and Breast...Breast Cancer Susceptibility...Other Susceptibility AllelesLow-Penetrance Breast Cancer...ConclusionReferences |
|---|
It is well understood that one of the most important risk factors for developing breast cancer is a family history of the disease. However, many other nongenetic risk factors contribute to disease etiology. They can be broadly categorized as hormonal and nonhormonal risk factors.
Hormonal Risk Factors
It has been shown repeatedly that estrogen exposure is directly associated with risk for developing breast cancer. A prolonged or increased exposure to estrogen is associated with an increased risk for developing breast cancer (3,4), whereas reducing exposure is thought to be protective [reviewed in (5)]. Therefore, factors that increase the number of menstrual cycles are associated with an increased likelihood for developing breast cancer, such as early age at menarche, nulliparity, and late onset of menopause (6–8). Similarly, it appears that decreasing the total number of ovulatory cycles can be protective, which can be achieved by moderate levels of exercise (9) and a longer lactation period (10).
There are discrepancies in the literature concerning the use of postmenopausal hormone replacement therapy as a risk factor for developing breast cancer. Overall, the incremental risk for breast cancer is small, but there is some evidence that suggests risk increases with long-term use [reviewed in (11,12)]. There also is evidence suggesting that age at first live birth can influence the risk for breast cancer development (13), with increasing maternal age at first live birth associated with an increasing risk for developing the disease. It has been hypothesized that these data suggest a protective effect of the terminal differentiation of breast epithelium associated with a full-term pregnancy and that this effect may be most protective at an early age.
Finally, there is an association between obesity and an increased breast cancer risk (14,15). The major source of estrogen in postmenopausal women is from the conversion of androstenedione to estrone by adipose tissue; thus, obesity is associated with a long-term increase in estrogen exposure.
Nonhormonal Risk Factors
A number of nonhormonal risk factors are associated with the development of breast cancer; however, some of these risk factors may be indirectly tied to modulation of estrogen exposure. One risk factor that is modified by the hormone milieu is the exposure to ionizing radiation. Young women who received mantle radiation for Hodgkin's lymphoma have a markedly increased risk for developing breast cancer, with an incidence ratio of 75.3 (16,17) as compared with age-matched control subjects. In addition, survivors of the atomic bomb blasts in Japan during the World War II have a very high incidence of breast cancer (18), likely because of somatic mutations introduced directly by radiation exposure. In both cases, it is postulated that exposure during adolescence, a period of active breast development, enhances the effect of radiation exposure (19,20).
Another nonhormonal risk factor may be alcohol consumption. A number of studies (21–23) have suggested that increased breast cancer risk is associated with both the amount and the duration of alcohol consumption. Nagata et al. (24) provided evidence that alcohol consumption can increase serum levels of estradiol, suggesting that alcohol consumption is indirectly associated with the development of breast cancer by increasing the exposure to estrogen.
Finally, evidence suggests that certain dietary factors may also contribute to an increased risk for developing breast cancer. Some of these dietary factors include high dietary fat (25,26) and "well-done" meat (27,28). The evidence for these factors increasing the risk for developing breast cancer is controversial because of study bias, discrepant data, and the inherent difficulties associated with collecting neonate dietary-exposure histories. Nevertheless, dietary fat intake may be a factor in indirectly increasing serum estrogen levels, and well-done meat may contain specific genotoxins. It is probable that nonhormonal risk factors contribute to breast cancer development in relationship to common variant alleles of a variety of genes (see below). As noted above, the manifestation of multifactorial diseases, such as breast cancer, is almost certainly reliant on the interplay between environmental and genetic factors.
|
BREAST CANCER SUSCEPTIBILITY GENES |
|---|
|
TopAbstractIntroductionRisk Factors and Breast...Breast Cancer Susceptibility...Other Susceptibility AllelesLow-Penetrance Breast Cancer...ConclusionReferences |
|---|
BRCA1 Gene
The first statistical evidence for an autosomal dominant breast cancer susceptibility gene with age-related penetrance was provided by Williams and Anderson (29). Using segregation analysis, they evaluated all genetic models that could explain the aggregation of breast cancer in these families and rejected all but inheritance of a highly penetrant autosomal susceptibility allele. This hypothesis was proven to be correct after the isolation of the first breast cancer susceptibility gene BRCA1 in 1994 (30). The BRCA1 gene was initially localized to chromosome 17q21 by genetic linkage of early-onset breast cancer families (31); it was later isolated by positional cloning by Miki et al. (30). Linkage between ovarian cancer and the BRCA1 locus was demonstrated (32) shortly after the chromosomal location was reported.
It is now known that germline mutations in BRCA1 represent a predisposing genetic factor in 15%–45% of hereditary breast cancers (depending on the population under study) and at least 80% of breast and/or ovarian cancers (33–35). Female mutation carriers have a 60%–80% lifetime risk for developing breast cancer (36,37) and a 20%–40% lifetime risk for developing ovarian cancer (37,38). Breast cancer in these families appears as a classic mendelian trait of autosomal dominance with high penetrance. Inherited breast cancer from germline mutations in BRCA1 has a number of distinguishing clinical features, such as an early age of onset compared with sporadic cases, a higher prevalence of bilateral breast cancer, and the presence of associated tumors in some affected individuals, specifically ovarian cancer and possibly colon and prostate cancers (39–41).
BRCA1 Gene Structure
BRCA1 is composed of 24 exons, 22 of which translate into a protein containing 1863 amino acids. The entire gene covers approximately 100 kilobases (kb) of genomic sequence. The coding region begins in exon 2; however, exon 4 is believed to be an artifact of the isolation method used and has been omitted from the gene sequence. BRCA1 is a novel gene with a C3HC4 zinc-binding RING-finger domain, which is situated at the amino terminus of the protein. In addition, BRCA1 has a classic simian virus 40-type nuclear localization sequence in exon 11 and a conserved acidic carboxyl terminus (30), now called the "BRCT" (BRCA1 carboxyl-terminal) domain (42,43). This region resembles the transactivation domain of a number of transcription factors (44) and contains two BRCT domains, which are situated in tandem at amino acids 1646–1736 and 1760–1855. Initially noted in BRCA1, BRCT motifs now have been described in a number of proteins that have a function in cell cycle control and DNA damage repair pathways (43,45), consistent with recent data suggesting an important role for BRCA1 in cellular responses to DNA damage.
Mutational Spectrum of BRCA1
Since the isolation of BRCA1, more than 500 sequence variations have been identified. Initially, eight disease-associated mutations were described within the gene (30,46), followed shortly by an increasing number of novel mutations (47–49). Most are frameshift mutations, but several missense mutations are known to alter protein function. Splice acceptor/donor sites are frequently mutated as well. Several specific classes of mutations with important clinical implications have been described since the BRCA1 gene was isolated.
Founder Mutations in BRCA1
Several founder mutations have been identified in BRCA1. The two most common mutations are 185delAG and 5382insC [reviewed in (50)], which account for approximately 10% of all the mutations seen in BRCA1. These two mutations occur at a 10-fold higher frequency in the Ashkenazi Jewish population (51,52) than in non-Jewish Caucasians. The carrier frequency of the 185delAG mutation in Ashkenazi Jews is approximately 1% (53) and, with the 5382insC mutation, account for almost all BRCA1 mutations in this population (54). The 185delAG mutation also has been found in non-Jewish populations, including Moroccan families (55) and, more recently, Spanish families (56), suggesting that this mutation arises in a mutational "hotspot" consistent with a short AG repeat at this locus. Analysis of germline mutations in Jewish and non-Jewish women with early-onset breast cancer indicates that approximately 20% of Jewish women who develop breast cancer before the age of 40 years carry the 185delAG mutation (57,58). It is interesting that the 5382insC mutation is the most common mutation in the only Russian series reported to date, and it has been found in families of European origin who are not aware of a Jewish background (59,60), but at a much lower frequency than in Ashkenazim.
The second most common mutation reported in the Russian population is the 4153delAA mutation [reviewed in (61)]. This mutation has not been seen outside Russia. One common mutation (2803delAA) has been seen in The Netherlands (62), and two founder mutations in the Norwegian population, 1675delA (63) and 1135insA (64), have been noted. Evidence for a new founder mutation among people of Scottish descent has been identified (65), with 2800delAA seen in seven of 17 families living in Scotland. The remaining families with this mutation had migrated to North America, but all had a clear preponderance of Scottish ancestry (66).
Large Genomic Deletions
Partial genomic deletions are an important source of mutation in BRCA1. It is presumed that this is due to a high frequency of Alu repeats in the intronic regions of BRCA1, facilitating inter-Alu recombination. Three large genomic deletions initially were identified in the Dutch/Belgian population; these deletions were estimated to account for 30% of all BRCA1 mutations in Dutch families (67) Additional deletions now have been characterized. Mazoyer and colleagues (68) have recently identified four novel deletions in the regulatory regions of the BRCA1 gene by screening French and U.S. families. This group (69) also has recently shown that Alu repeats contribute to insertions in BRCA1, and they suggest that the presence of a 6-kb Alu-mediated duplication is a founder mutation among families of European descent.
Function of BRCA1
BRCA1 was predicted to be a tumor suppressor gene even before it was isolated because of the frequent loss of heterozygosity of wild-type alleles of chromosome 17q in BRCA1-associated tumors (70,71). These data suggest that malignancy occurs when both functional alleles of BRCA1 are lost, which is characteristic of tumor suppressor genes.
Data accumulated since the isolation of the BRCA1 gene suggest a role in transcription, cell cycle control, and DNA damage repair pathways. Supporting a role for BRCA1 in transcription is the observation that the BRCA1 protein can interact with the basal transcriptional machinery (RNA polymerase II, transcription factors TFIIH and TFIIE, and RNA helicase A) (72,73), as well as enhance p53 transactivation. In addition, evidence for a DNA damage response-associated role for BRCA1 initially came from Livingston and colleagues (74), who demonstrated that BRCA1 is part of subnuclear foci known to contain Rad51. Rad51 is the human homologue of the yeast DNA damage checkpoint gene of the same name, thought to be involved in homologous recombination and double-strand break repair. Recently, it has been shown that BRCA1 and BRCA2 proteins co-localize in subnuclear foci on the axial elements of developing synaptonemal complexes in meiotic cells (75). Therefore, it is believed that BRCA1 and BRCA2 proteins participate in a common DNA damage response pathway associated with homologous recombination and double-strand break repair.
Recent evidence for the role of BRCA1 in cell cycle checkpoints is the association of the BRCA1 protein with the centrosome and a role for BRCA1 in centrosome amplification and the G2/M checkpoint (76,77). Initially, Hsu and White (76) demonstrated that the BRCA1 protein associates with 
-tubulin (a component of the centrosome) during mitosis. It is interesting that a number of additional cell cycle regulatory proteins have also been shown to localize to the centrosome, particularly cyclin A, cyclin B (78), and cdc2 (79,80). In addition, p53 has been shown to associate with the centrosome (81), and p53 nullizygous mouse embryonic fibroblasts have a high frequency of amplified centrosomes and aberrant mitoses leading to chromosome instability (82). More recently, Carroll et al. (83) also demonstrated that centrosome hyperamplification is frequent in advanced-stage breast carcinomas.
The BRCA1 protein also is postulated to play a role in regulating apoptotic cell death. Initial experiments by Rao and colleagues (84) involved transfecting mouse fibroblast cell lines and human breast cancer cell lines with BRCA1. They demonstrated that a BRCA1 complementary DNA (cDNA) corresponding to the exon 11 splice variant (deletion of exon 11) produced a flattened cell morphology and induced apoptosis after serum deprivation or calcium ionophore treatment. More recently, using oligonucleotide arrays and functional assays, Haber and colleagues (85) demonstrated induction of BRCA1-triggered apoptosis after activation of the c-Jun N-terminal kinase/stress-activated protein kinase (JNK/SAPK), a pathway believed to be linked to GADD45 gene family members. GADD45 induction was independent of p53, suggesting a pathway for BRCA1-induced apoptotic cell death.
The most direct evidence that BRCA1 is involved in response to DNA damage is that mouse embryonic stem cells nullizygous for Brca1 are defective in transcription-coupled repair and are hypersensitive to ionizing radiation or oxidative damage (86). These data indicate that BRCA1 participates either directly or indirectly in cellular responses to DNA damage. Moreover, Holt and colleagues (87) showed that human HCC1937 cells (containing only mutant BRCA1) are hypersensitive to ionizing radiation and are defective for transcription-coupled repair but not for double-strand break repair, although this cell line contains mutations in numerous other genes, which limits the conclusions that can be drawn. In summary, all functional data on BRCA1 to date can be reconciled by postulating that BRCA1 functions as a sensor of DNA damage, triggering critical pathways of cell cycle arrest or apoptotic cell death, by acting as a coactivator of transcription factors. However, much more work needs to be done in this regard.
BRCA2 Gene
Evidence for a second dominant breast cancer susceptibility gene emerged from a linkage analysis of 22 families with multiple cases of early-onset female breast cancer and at least one case of male breast cancer. Twelve of these families also had at least one member with ovarian cancer. With the use of these families, linkage was established between polymorphic markers on chromosome 13q12–13 and the BRCA2 locus (88). As with BRCA1 mutation carriers, the lifetime breast cancer risk for BRCA2 mutation carriers is estimated to be in the range of 60%–85%, and the lifetime ovarian cancer risk is estimated to be in the range of 10%–20% (89,90). Unlike male carriers of BRCA1 mutations, men with germline mutations in BRCA2 have an estimated 6% lifetime breast cancer risk, representing a 100-fold increase over the male population risk. BRCA2 mutations also may be associated with an increase in colon, prostate, pancreatic, gallbladder, bile duct, and stomach cancers as well as malignant melanoma (91,92).
Structure of BRCA2
BRCA2 was identified in 1995 (93), and the complete cDNA sequence of BRCA2 was published by a collaborative group in 1996 (94). The BRCA2 cDNA is approximately 11.5 kb long and is contained within 70 kb of genomic DNA. The 11.2-kb coding region is composed of 26 exons. Exon 1 is untranslated. The BRCA2 protein consists of 3418 amino acids, with an estimated molecular mass of 384 kd. The BRCA2 gene bears no obvious homology to any previously described gene, and the protein contains no previously defined functional domains. There are eight copies of a 30- to 80-amino acid repeat (BRC repeats) that are present in the part of the protein encoded by exon 11, conserved between species, and postulated to facilitate the binding of Rad51 to the BRCA2 protein (95,96).
Mutational Spectrum of BRCA2
The mutational spectrum of BRCA2 is not as well established as that of BRCA1, but it is being defined at a rapid rate. To date, more than 250 mutations have been found (91,93,94,97–104), and a tabulated list is available in the BIC (i.e., Breast Cancer Information Core) website: http://www.nhgri.nih.gov/Intramural_research/Lab_transfer/Bic/Member/index.html). Mutations are spread throughout the gene. To date, no mutation hotspots have been found. In addition, no BRCA2 missense mutations have been unequivocally designated as disease associated because of the paucity of data on functional domains of this protein. All definitively disease-associated mutations in BRCA2 result in a truncated protein.
Founder Mutations in BRCA2
A number of founder mutations have been identified in BRCA2. The 6174delT mutation is found in Ashkenazi Jews with a prevalence of 1.2% (105). Initial penetrance estimates for this mutation approached 60% (52), but a recent study by Fodor et al. (106) suggested that the lifetime risk for breast cancer in Ashkenazi Jewish carriers of this mutation may be as low as 36%, an indication that there may be subpopulation differences. Another BRCA2 founder mutation, 999del5, has been observed in Icelandic and Finnish populations (107,108). Families from both countries were studied to determine the relationship between the Icelandic 999del5 mutation and the Finnish 999del5. A common haplotype that covered a region spanning the BRCA2 gene was found to be shared by the Icelandic and the Finnish mutation carriers (108), suggesting that this mutation was carried by individuals who migrated from Finland to Iceland during ancient times [reviewed in (61)].
Function of BRCA2
The biologic function of BRCA2 is not well defined; however, like BRCA1, BRCA2 is postulated to play a role in DNA damage response pathways. BRCA2 binds Rad51, the human homologue of the RecA protein in Escherichia coli and the ScRad51 protein in budding yeast (Saccharomyces cerevisiae). ScRad51 is involved in mitotic and meiotic recombinations and double-strand break repair (109). Rad51 binds to the BRC repeats in BRCA2 (110) and the carboxyl-terminal domain of BRCA2 (111). BRCA2 is a nuclear protein (111,112) and, as noted above, BRCA1 and BRCA2 have recently been shown to interact with one another and to co-localize to the nuclei of cells, confirming their function in some of the same cellular pathways (75).
BRCA2 messenger RNA is expressed at higher levels in late G1 and S phases of the cell cycle. The kinetics of BRCA2 protein regulation in the cell cycle is similar to that of BRCA1 protein, suggesting that these genes are coordinately regulated (113). Also like BRCA1, BRCA2 is localized in the nucleus in response to cell proliferation, and BRCA2 is expressed before DNA synthesis begins (112).
|
OTHER SUSCEPTIBILITY ALLELES |
|---|
|
TopAbstractIntroductionRisk Factors and Breast...Breast Cancer Susceptibility...Other Susceptibility AllelesLow-Penetrance Breast Cancer...ConclusionReferences |
|---|
p53 and Li–Fraumeni Syndrome
The first documentation of Li–Fraumeni syndrome was in 1969, in which four families with children with soft-tissue sarcomas were found to have an excess of sarcomas in other relatives. In addition, these families exhibited an excess of early-onset breast cancer and other cancers, such as childhood leukemia, adrenocortical carcinoma, and brain cancer (114). In 1990, Malkin et al. (115) reported the presence of germline p53 mutations in approximately half of families with classic Li–Fraumeni syndrome. In women with germline p53 mutations who survive childhood cancers, it is estimated that 50% will have developed breast cancer by the age of 50 years (34), and lifetime penetrance approaches 100%. Prevalence studies of germline p53 mutations in unselected women with breast cancer (34,116) have found germline mutations in less than 1% of women. Therefore, p53 germline mutations are thought to be a rare cause of breast cancer, except in the setting of Li–Fraumeni syndrome.
STK11/LKB1 and Peutz–Jeghers Syndrome
Peutz–Jeghers syndrome is caused by germline mutations in STK11/LKB1, a serine–threonine kinase located on chromosome 19q13.3 (117,118). Peutz–Jeghers syndrome is characterized by hamartomatous polyps in the small bowel and pigmented macules of the buccal mucosa, lips, fingers, and toes. A retrospective study looking at cancer risk in Peutz–Jeghers families (119) assigns a relative risk for breast cancer of 20.3. The mean age of patients at breast cancer diagnosis in this series was 39 years. In spite of the early-onset breast cancer that can be seen in patients with Peutz–Jeghers syndrome, mutations in STK11/LKB1 do not appear to play an important role in sporadic breast cancers, based on the very low prevalence of mutations in the population (120).
PTEN and Cowden Syndrome
Cowden syndrome is a rare autosomal dominant predisposition to both benign and malignant neoplasms. Breast cancer develops in 20%–30% of carrier women. Other tumors seen among patients with Cowden syndrome include adenomas and follicular cell carcinomas of the thyroid gland, polyps and adenocarcinomas of the gastrointestinal tract, and ovarian cysts and carcinoma (121,122). Cowden syndrome is caused by germline mutations in the PTEN gene (MMAC1/TEP1). PTEN, a tumor suppressor gene on 10q23.3 (123–125), is a dual-specificity phosphatase (126).
Because of the increased incidence of breast cancer among female patients with Cowden syndrome, there was speculation that PTEN would play a role in familial breast cancer (127,128). However, in families with a high incidence of breast cancer but without linkage to BRCA1 or BRCA2, linkage to the PTEN gene has not been found (129). No PTEN germline mutations have been found in BRCA1-negative women diagnosed with breast cancer before the age of 35 years (130,131). Similarly, no germline mutations in the PTEN gene have been found in women diagnosed with breast cancer who do not carry mutations in BRCA1 and/or BRCA2 but who do have a clinically significant family history of breast cancer (132). Therefore, these data strongly suggest that PTEN does not play a role in familial breast cancer, apart from its role in Cowden syndrome. Of note, there is a common insertion polymorphism in PTEN, downstream of exon 4, that was associated with early age of breast cancer diagnosis in one study (
21 = 0.024) among patients who are homozygous for the insertion. These preliminary data suggest that this variant may be a low-penetrance susceptibility allele, but additional work will be needed to confirm this observation (132).
MSH2/MLH1 and Muir–Torre Syndrome
Muir–Torre syndrome is defined by the presence of sebaceous gland tumors and visceral malignancy. It is inherited in an autosomal dominant fashion with high penetrance (133) because of mutations in the same genes associated with hereditary nonpolyposis colorectal cancer (HNPCC). The most common malignancy in Muir–Torre syndrome is colorectal cancer, seen in 50% of patients, but breast cancer occurs in approximately 25% of women carriers. The median age of the patients diagnosed with breast cancer is 68 years (134). As in HNPCC, microsatellite instability is observed in the tumors of patients with Muir–Torre syndrome. Mutational analysis in Muir–Torre syndrome kindreds now has demonstrated mutations predominantly in MSH2 but with two families with mutations in MLH1.
ATM and Ataxia-telangiectasia
Ataxia-telangiectasia (AT) is a complex, autosomal recessive disorder characterized by cerebellar ataxia, telangiectasia, immunodeficiencies, radiation sensitivity, and cancer predisposition, caused by homozygous mutations in the ATM gene. Epidemiologic studies of AT families (135–143) suggest that AT carriers (heterozygotes) may have an increased risk for developing breast cancer, although this observation is controversial. A number of studies (140,142) have estimated the relative risk of breast cancer among AT carriers and suggest it to be between 3.3 and 3.9. At a recent workshop on the incidence of breast cancer among AT patients [reviewed in (144)], Borresen-Dale and colleagues presented evidence in support of the hypothesis of an increased incidence of breast cancer among AT heterozygotes. They reported the incidence of breast cancer in Scandinavia to be almost eight times higher in mothers of AT patients than in the general population [reviewed in (144)]. In addition, one study [reviewed in (144)] showed that 9% of patients with early-onset breast cancer had germline ATM mutations. However, another study (141) did not find an increased prevalence of ATM mutations in breast cancer patients. Although there is mounting evidence that there is an increased risk for breast cancer among AT heterozygotes, this issue has yet to be resolved. In addition, it has been suggested that missense mutations in ATM may be associated with a milder phenotype than truncating mutations (145). The validity of ATM as a breast cancer susceptibility gene warrants further consideration, but it may be best characterized as a low-penetrance or modifier gene.
|
LOW-PENETRANCE BREAST CANCER SUSCEPTIBILITY GENES |
|---|
|
TopAbstractIntroductionRisk Factors and Breast...Breast Cancer Susceptibility...Other Susceptibility AllelesLow-Penetrance Breast Cancer...ConclusionReferences |
|---|
Low-penetrance susceptibility alleles, sometimes called "modifier genes," are defined as polymorphic genes with specific alleles that are associated with an altered risk for disease susceptibility. Usually, the variants in these genes are common in the general population. Therefore, although each variant may be associated with a small increased risk for breast cancer in an individual, the attributable risk in the population as a whole is likely to be higher than for rare, high-penetrance susceptibility genes. Candidate modifier genes are chosen on the basis of biologic plausibility. Methods to identify novel modifier genes are under development. Modifier genes may be found in a number of pathways, including detoxification of environmental carcinogens, steroid metabolism pathways, DNA damage response pathways, and immunomodulatory pathways.
Modifier genes can be evaluated in several ways. First, in an unselected population, sequence variants in candidate modifier genes can be assayed for association with an increased risk for developing breast cancer. Second, in carriers of mutations in autosomal dominant high-penetrance genes, which confer a high risk of cancer but have some variability in penetrance, the same polymorphisms in low-penetrance genes can modify different phenotypes, such as the age at diagnosis of breast cancer. The following sections summarize some of the candidate modifier genes currently being evaluated. In addition, one of these sections will outline how a rat model for inducible mammary carcinoma is a useful paradigm for identifying novel low-penetrance genes for breast cancer.
The P450 Gene CYP1A1
CYP1A1 encodes aryl hydrocarbon hydroxylase, which is the primary catalyst in the conversion of estradiol to hydroxylated (catechol) estrogen (146). As previously mentioned, a reduced estrogen exposure is protective for developing breast cancer, whereas increased estrogen exposure can increase the risk for developing breast cancer. Therefore, alterations in the activity of aryl hydrocarbon hydroxylase could plausibly lead to a change in the levels of estrogen and, ultimately, could affect breast cancer risk.
A number of polymorphisms in CYP1A1 have been investigated in relation to their association with breast cancer risk. One point mutation in the heme-binding catalytic site of exon 7, which substitutes a valine for an isoleucine, has been shown to be associated with increased enzyme activity (147). In addition, an MspI restriction fragment-length polymorphism exists in the 3` noncoding region of the gene. In a small preliminary study (148), the MspI allele was shown to be associated with increased breast cancer risk among African-Americans. However, a follow-up case–control study indicated that there was no association with breast cancer risk and the MspI allele.
Because CYP1A1 has been shown to catalyze endogenous estrogen metabolism, the association of variant CYP1A1 alleles, estrogen metabolism, and breast cancer risk has been recently investigated (149). In a small case–control study, Taioli et al. (149) demonstrated that the frequency of the homozygous MspI polymorphism was greater among African-Americans with breast cancer than among Caucasian women with breast cancer; they found a striking odds ratio of 8.4 in homozygous MspI variant carriers. No significant risk was associated with heterozygote carriers of the variant allele.
Finally, in experimental systems, polychlorinated biphenyls (PCBs) can induce CYP1A1. Therefore, the association between breast cancer risk and exposure to PCBs has also been investigated. Moysich et al. (150) investigated the role of the exon 7 point mutation in relation to an increased risk of breast cancer in postmenopausal women, when PCB body burden was taken into consideration. Women who were heterozygous for the variant allele and who had an increased exposure to PCBs were at an increased risk of breast cancer. The authors postulate that this CYP1A1 genotype may modify the effect of PCBs on the risk of breast cancer in postmenopausal women through increased CYP1A1 enzyme induction or by activation by specific PCB congeners.
Glutathione S-Transferases
The glutathione S-transferases (GSTs) constitute a family of genes that encode for enzymes that catalyze the conjunction of reactive chemical intermediates to soluble glutathione conjugates to facilitate clearance. There are four classes (
, µ, 
, and 
) of cytosolic GSTs, of which at least three are expressed in normal breast tissue (151). The GSTµ (GSTM and GST (GSTT) genes have a null polymorphism that results in a total lack of enzyme in 50% of the population. There has been interest in determining whether homozygotes for the null alleles in GSTT1 or GSTM1 have an increased risk of breast cancer because the enzymes metabolize environmental carcinogens (152). Rebbeck et al. (153) have demonstrated that GSTM1 and GSTT1 are associated with variability in age at first breast cancer diagnosis in BRCA1 mutation carriers, with a 22% difference across the observed age range (25–40 years) by the GSTT1 genotype. These findings suggest that the inability to metabolize carcinogens by way of GSTT1 may increase breast cancer risk.
However, in a recent study of diet and cancer in western New York (154), the GSTM1 genotype of women with confirmed breast cancer and community control women was determined. The null allele was not associated with an increased breast cancer risk, regardless of menopausal status. In addition, no difference in associations between the polymorphism and risk among lower and higher consumers of dietary sources of antioxidants or smokers and nonsmokers was observed. In contrast to the previous studies, the authors (154) concluded that GSTM1 genetic polymorphisms are not associated with breast cancer risk, even in an environment low in antioxidant defenses. Further analysis of these genes should clarify their role in breast cancer risk.
N-Acetyltransferase
The relationship between age-specific breast cancer penetrance stratified by smoking and acetylation status conferred by N-acetyltransferase 2 (NAT2), another important component of the carcinogen metabolism pathway, has been investigated. Polymorphisms in the NAT2 gene are associated with an altered rate of metabolism of carcinogens. Wild-type alleles define a rapid acetylator phenotype, whereas homozygosity for any combination of three variant alleles results in a slow acetylator phenotype. Thus, having a slow phenotype could lead to a slower metabolism of carcinogenic amines. It has been suggested that breast cancer penetrance is not statistically significantly higher among slow acetylators (those that clear carcinogens more slowly) when evaluated as a single parameter (155). However, Rebbeck and colleagues (156) have shown that there is a statistically significant interaction between acetylation status among BRCA1 carriers and the number of packs of cigarettes that they smoked per week, duration of time that they smoked, or the age at which they started to smoke. These findings suggest that BRCA1 mutation carriers who smoke are at an increased risk for breast cancer if they are also slow acetylators. An association between smoking and altered steroid hormone metabolism could be the explanation for these findings.
Although inconsistencies exist, some studies have shown that red meat consumption is associated with increased breast cancer risk (27). Heterocyclic amines are activated by polymorphic NAT2; thus, rapid NAT2 activity may increase risk associated with heterocyclic amines. In one study, Ambrosone et al. (157) found that there was no relationship between the risk of breast cancer and the ingestion of meat, poultry, and fish and particular concentrated sources of heterocyclic amines. In addition, NAT2 genotype alone does not modify breast cancer risk in this study. The authors conclude that the polymorphic NAT2 genotype may have an impact only on breast cancer risk if it is in conjunction with another polymorphic genotype (e.g., CYP1A2). This phenomenon has been seen previously in association with CYP1A2 genotype in a study of colon cancer (158). Further studies are necessary to determine the role of NAT2 in breast cancer.
Androgen Receptor
The effect of the CAG microsatellite found in exon 1 of the androgen receptor gene has been investigated for its role in breast cancer penetrance in BRCA1 mutation carriers. Androgen receptor alleles containing longer CAG repeat lengths are associated with a decreased ability to activate androgen-responsive genes. Rebbeck et al. (159) found that BRCA1 mutation carriers who carry at least one androgen receptor allele with more than 29 CAG repeats were diagnosed with breast cancer statistically significantly earlier than women with shorter CAG repeats in their androgen receptor genes, suggesting that pathways involving androgen signaling may affect the penetrance of BRCA1-associated breast cancer.
Rat Models and Candidate Genes
The rat is an extremely valuable model for studying susceptibility to many diseases, including breast cancer, particularly given that the characteristics of rat mammary cancer are remarkably similar to those of breast cancer in humans. Specifically, inducible rat carcinoma emulates the histopathology of cancer progression in human breast cancer. In addition, mammary cancer in the rat model is responsive to hormone therapy (160). Several rat models exist to study mammary carcinogenesis susceptibility and resistance, including the tumor-resistant Copenhagen (COP) strain, which carries dominant-resistant genes, and the Wistar-Furth (WF) strain, which is susceptible to inducible carcinoma of the mammary gland [reviewed in (161)]. Although these models use a system of induction, the use of chemical perturbants in animal models could be compared with environmental factors that influence disease susceptibility with a variability that depends on the genetic background. Thus, the ability to backcross susceptible strains onto a resistant background provides an excellent paradigm for mapping novel, modifier genes.
For example, in an initial (WF x COP)F1 x WF backcross, the first mammary carcinoma susceptibility locus (Mcs1) was identified on rat chromosome 2 (162). Recently, Gould and colleagues (163) expanded the initial study and performed a genome-wide screen of the original backcross, as well as generating and screening a second backcross and an F2 intercross between COP and WF rats. In this study, the investigators confirmed the identification of the Mcs1 locus and identified three additional loci that modify the susceptibility to 7,12-dimethylbenz[a]anthracene (DMBA)-induced breast cancer. They have designated these loci Mcs2, Mcs3, and Mcs4, which are located on rat chromosomes 7, 1, and 8, respectively (163). It is interesting that Mcs4 is located on rat chromosome 8 and is linked to the cytochrome P450 genes Cyp1a1 and CypD45. As noted above, this observation is of particular interest because CYP1A1 has been suggested to be a low-penetrance or "modifier" gene of human breast cancer (147). The fact that Mcs4 is linked to a candidate modifier gene of breast cancer in humans further validates this model for studying the genetics of breast cancer. It is hoped that the identification of genes in murine models will provide a means to identify candidate genes in the human counterpart, which will aid our understanding of human diseases (164).
Despite numerous studies published to date, the role of modifier genes in breast cancer susceptibility remains to be elucidated. The resolution of ambiguous results will require further, carefully designed studies with sufficient sample sizes to detect small effects.
|
CONCLUSION |
|---|
|
TopAbstractIntroductionRisk Factors and Breast...Breast Cancer Susceptibility...Other Susceptibility AllelesLow-Penetrance Breast Cancer...ConclusionReferences |
|---|
Further analysis of BRCA1, BRCA2, and other breast cancer susceptibility genes will allow the elucidation of the pathogenesis of this disease. The use of animal models will become increasingly important in this endeavor. Great strides have already been made in determining the disease etiology, but further investigation is necessary. Recent attention has focused on the use of whole-genome linkage disequilibrium studies to map common disease genes. These studies use single nucleotide polymorphisms to detect associations between a marker/gene and a particular disease (165). Single nucleotide polymorphisms are an abundant form of genetic variants and are distinguished from rare variants by a requirement for the least abundant variant allele to have a frequency of 1% or more (166). The use of single nucleotide polymorphisms, in conjunction with a range of studies involving animal models and genetic epidemiologic methodology, will facilitate the genetic analysis of complex diseases, such as breast cancer, and promise to yield a vast array of information. These studies will be crucial to evaluate the importance of new genes involved in breast cancer etiology, so that scientists can define better therapies and cancer prevention.
|
REFERENCES |
|---|
|
TopAbstractIntroductionRisk Factors and Breast...Breast Cancer Susceptibility...Other Susceptibility AllelesLow-Penetrance Breast Cancer...ConclusionReferences |
|---|
1
Kelsey JL, Horn-Ross PL. Breast cancer: magnitude of the problem and descriptive epidemiology. Epidemiol Rev 1993;15:7–16.
2 Claus EB, Schildkraut JM, Thompson WD, Risch NJ. The genetic attributable risk of breast and ovarian cancer. Cancer 1996;77:2318–24.[CrossRef][ISI][Medline]cancerlit;96224900
3 Begg L, Kuller LH, Gutai JP, Caggiula AG, Wolmark N, Watson CG. Endogenous sex hormone levels and breast cancer risk. Genet Epidemiol 1987;4:233–47.[CrossRef][ISI][Medline]cancerlit;88030628
4 Pike MC, Gerkins VR, Casagrande JT, Gray GE, Brown J, Henderson BE. The hormonal basis of breast cancer. Natl Cancer Inst Monogr 1979;53:187–93.
5 Hulka BS. Epidemiologic analysis of breast and gynecologic cancers. Prog Clin Biol Res 1997;396:17–29.[ISI][Medline]cancerlit;97262204
6 Trichopoulos D, MacMahon B, Cole P. Menopause and breast cancer risk. J Natl Cancer Inst 1972;48:605–13.
7
Kampert JB, Whittemore AS, Paffenbarger RS Jr. Combined effect of childbearing, menstrual events, and body size on age-specific breast cancer risk. Am J Epidemiol 1988;128:962–79.
8
White E. Projected changes in breast cancer incidence due to the trend toward delayed childbearing. Am J Public Health 1987;77:495–7.
9
Bernstein L, Henderson BE, Hanisch R, Sullivan-Halley J, Ross RK. Physical exercise and reduced risk of breast cancer in young women. J Natl Cancer Inst 1994;86:1403–8.
10
Yuan JM, Yu MC, Ross RK, Gao YT, Henderson BE. Risk factors for breast cancer in Chinese women in Shanghai. Cancer Res 1988;48:1949–53.
11 Agarwal SK, Judd HL. Estrogen replacement therapy and breast cancer [editorial]. Fertil Steril 1999;71:602–3.[CrossRef][ISI][Medline]cancerlit;99217515
12 Steinberg KK, Thacker SB, Smith SJ, Stroup DF, Zack MM, Flanders WD, et al. A meta-analysis of the effect of estrogen replacement therapy on the risk of breast cancer [published erratum appears in JAMA 1991;266:1362]. JAMA 1991;265:1985–90.[Abstract]cancerlit;91178879
13 MacMahon B, Cole P, Lin TM, Lowe CR, Mirra AP, Ravnihar B, et al. Age at first birth and breast cancer risk. Bull World Health Organ 1970;43:209–21.[ISI][Medline]
14
Paffenbarger RS Jr, Kampert JB, Chang HG. Characteristics that predict risk of breast cancer before and after the menopause. Am J Epidemiol 1980;112:258–68.
15 Pujol P, Galtier-Dereure F, Bringer J. Obesity and breast cancer risk. Hum Reprod 1997;12 Suppl 1:116–25.cancerlit;98067032
16
Bhatia S, Robison LL, Oberlin O, Greenberg M, Bunin G, Fossati-Bellani F, et al. Breast cancer and other second neoplasms after childhood Hodgkin's disease. N Engl J Med 1996;334:745–51.
17 Wolden SL, Lamborn KR, Cleary SF, Tate DJ, Donaldson SS. Second cancers following pediatric Hodgkin's disease. J Clin Oncol 1998;16:536–44.[Abstract]cancerlit;98129240
18 Land CE. Studies of cancer and radiation dose among atomic bomb survivors. The example of breast cancer. JAMA 1995;274:402–7.[Abstract]cancerlit;95341751
19 Tokunaga M, Land CE, Tokuoka S, Nishimori I, Soda M, Akiba S. Incidence of female breast cancer among atomic bomb survivors, 1950–1985. Radiat Res 1994;138:209–23.[ISI][Medline]cancerlit;94240220
20
Goss PE, Sierra S. Current perspectives on radiation-induced breast cancer. J Clin Oncol 1998;16:338–47.
21
Bowlin SJ, Leske MC, Varma A, Nasca P, Weinstein A, Caplan L. Breast cancer risk and alcohol consumption: results from a large case–control study. Int J Epidemiol 1997;26:915–23.
22 Garfinkel L, Boffetta P, Stellman SD. Alcohol and breast cancer: a cohort study. Prev Med 1988;17:686–93.[CrossRef][ISI][Medline]cancerlit;89220868
23 Ewertz M. Alcohol consumption and breast cancer risk in Denmark. Cancer Causes Control 1991;2:247–52.[CrossRef][ISI][Medline]cancerlit;91338419
24 Nagata C, Kabuto M, Takatsuka N, Shimizu H. Associations of alcohol, height, and reproductive factors with serum hormone concentrations in postmenopausal Japanese women. Steroid hormones in Japanese postmenopausal women. Breast Cancer Res Treat 1997;44:235–41.[CrossRef][ISI][Medline]
25
Wynder EL, Cohen LA, Muscat JE, Winters B, Dwyer JT, Blackburn G. Breast cancer: weighing the evidence for a promoting role of dietary fat. J Natl Cancer Inst 1997;89:766–75.
26 Boyd NF, Martin LJ, Noffel M, Lockwood GA, Trichler DL. A meta-analysis of studies of dietary fat and breast cancer risk. Br J Cancer 1993;68:627–36.[ISI][Medline]cancerlit;93357165
27
Zheng W, Gustafson DR, Sinha R, Cerhan JR, Moore D, Hong CP, et al. Well-done meat intake and the risk of breast cancer. J Natl Cancer Inst 1998;90:1724–9.
28
Zheng W, Deitz AC, Campbell DR, Wen WQ, Cerhan JR, Sellers TA, et al. N-Acetyltransferase 1 genetic polymorphism, cigarette smoking, well-done meat intake, and breast cancer risk. Cancer Epidemiol Biomarkers Prev 1999;8:233–9.
29 Williams WR, Anderson DE. Genetic epidemiology of breast cancer: segregation analysis of 200 Danish pedigrees. Genet Epidemiol 1984;1:7–20.[CrossRef][Medline]cancerlit;86031251
30
Miki Y, Swensen J, Shattuck-Eidens D, Futreal PA, Harshman K, Tavtigian S, et al. A strong candidate for the breast and ovarian cancer susceptibility gene BRCA1. Science 1994;266:66–71.
31
Hall JM, Lee MK, Newman B, Morrow JE, Anderson LA, Huey B, et al. Linkage of early-onset familial breast cancer to chromosome 17q21. Science 1990;250:1684–9.
32 Narod SA, Feunteun J, Lynch HT, Watson P, Conway T, Lynch J, et al. Familial breast–ovarian cancer locus on chromosome 17q12–q23. Lancet 1991;338:82–3.[CrossRef][ISI][Medline]cancerlit;91287429
33 Narod SA, Ford D, Devilee P, Barkardottir RB, Lynch HT, Smith SA, et al. An evaluation of genetic heterogeneity in 145 breast–ovarian cancer families. Breast Cancer Linkage Consortium. Am J Hum Genet 1995;56:254–64.[ISI][Medline]cancerlit;95126120
34 Easton D, Ford D, Peto J. Inherited susceptibility to breast cancer. Cancer Surv 1993;18:95–113.[ISI][Medline]cancerlit;94282794
35
Couch FJ, DeShano ML, Blackwood MA, Calzone K, Stopfer J, Campeau L, et al. BRCA1 mutations in women attending clinics that evaluate the risk of breast cancer. N Engl J Med 1997;336:1409–15.
36 Easton DF, Bishop DT, Ford D, Crockford GP. Genetic linkage analysis in familial breast and ovarian cancer: results from 214 families. The Breast Cancer Linkage Consortium. Am J Hum Genet 1993;52:678–701.[ISI][Medline]cancerlit;93212726
37 Struewing JP, Tarone RE, Brody LC, Li FP, Boice JD Jr. BRCA1 mutations in young women with breast cancer [letter]. Lancet 1996;347:1493.[ISI][Medline]cancerlit;96225393
38 Easton DF, Ford D, Bishop DT. Breast and ovarian cancer incidence in BRCA1-mutation carriers. Breast Cancer Linkage Consortium. Am J Hum Genet 1995;56:265–71.[ISI][Medline]cancerlit;95126121
39 Nelson CL, Sellers TA, Rich SS, Potter JD, McGovern PG, Kushi LH. Familial clustering of colon, breast, uterine, and ovarian cancers as assessed by family history. Genet Epidemiol 1993;10:235–44.[CrossRef][ISI][Medline]cancerlit;94040671
40 Anderson DE, Badzioch MD. Familial breast cancer risks. Effects of prostate and other cancers. Cancer 1993;72:114–9.[CrossRef][ISI][Medline]cancerlit;93284559
41 Arason A, Barkardottir RB, Egilsson V. Linkage analysis of chromosome 17q markers and breast–ovarian cancer in Icelandic families, and possible relationship to prostatic cancer. Am J Hum Genet 1993;52:711–7.[ISI][Medline]cancerlit;93212728
42 Koonin EV, Altschul SF, Bork P. BRCA1 protein products: functional motifs. Nat Genet 1996;13:266–8.[CrossRef][ISI][Medline]cancerlit;96259550
43 Callebaut I, Mornon JP. From BRCA1 to RAP1: a widespread BRCT module closely associated with DNA repair. FEBS Lett 1997;400:25–30.[CrossRef][ISI][Medline]
44
Abel KJ, Xu J, Yin GY, Lyons RH, Meisler MH, Weber BL. Mouse Brca1: localization sequence analysis and identification of evolutionarily conserved domains. Hum Mol Genet 1995;4:2265–73.
45 Bork P, Hofmann K, Bucher P, Neuwald AF, Altschul SF, Koonin EV. A superfamily of conserved domains in DNA damage-responsive cell cycle checkpoint proteins. FASEB J 1997;11:68–76.[Abstract]cancerlit;97186552
46
Futreal PA, Liu Q, Shattuck-Eidens D, Cochran C, Harshman K, Tavtigian S, et al. BRCA1 mutations in primary breast and ovarian carcinomas. Science 1994;266:120–2.
47 Castilla LH, Couch FJ, Erdos MR, Hoskins KF, Calzone K, Garber JE, et al. Mutations in the BRCA1 gene in families with early-onset breast and ovarian cancer. Nat Genet 1994;8:387–91.[CrossRef][ISI][Medline]cancerlit;95201806
48 Friedman LS, Ostermeyer EA, Szabo CI, Dowd P, Lynch ED, Rowell SE, et al. Confirmation of BRCA1 by analysis of germline mutations linked to breast and ovarian cancer in ten families. Nat Genet 1994;8:399–404.[CrossRef][ISI][Medline]cancerlit;95201808
49 Simard J, Tonin P, Durocher F, Morgan K, Rommens J, Gingras S, et al. Common origins of BRCA1 mutations in Canadian breast and ovarian cancer families. Nat Genet 1994;8:392–8.[CrossRef][ISI][Medline]cancerlit;95201807
50 Couch FJ, Weber BL. Mutations and polymorphisms in the familial early-onset breast cancer (BRCA1) gene. Breast Cancer Information Core. Hum Mutat 1996;8:8–18.[CrossRef][ISI][Medline]cancerlit;96400954
51 Tonin P, Serova O, Lenoir G, Lynch H, Durocher F, Simard J, et al. BRCA1 mutations in Ashkenazi Jewish women [letter]. Am J Hum Genet 1995;57:189.[ISI][Medline]cancerlit;95335673
52
Struewing JP, Hartge P, Wacholder S, Baker SM, Berlin M, McAdams M, et al. The risk of cancer associated with specific mutations of BRCA1 and BRCA2 among Ashkenazi Jews. N Engl J Med 1997;336:1401–8.
53 Roa BB, Boyd AA, Volcik K, Richards CS. Ashkenazi Jewish population frequencies for common mutations in BRCA1 and BRCA2. Nat Genet 1996;14:185–7.[CrossRef][ISI][Medline]cancerlit;96438856
54 Berman DB, Wagner-Costalas J, Schultz DC, Lynch HT, Daly M, Godwin AK. Two distinct origins of a common BRCA1 mutation in breast– ovarian cancer families: a genetic study of 15 185delAG-mutation kindreds. Am J Hum Genet 1996;58:1166–76.[ISI][Medline]cancerlit;96213751
55
Bar-Sade RB, Kruglikova A, Modan B, Gak E, Hirsh-Yechezkel G, Theodor L, et al. The 185delAG BRCA1 mutation originated before the dispersion of Jews in the diaspora and is not limited to Ashkenazim. Hum Mol Genet 1998;7:801–5.
56 Diez O, Osorio A, Robledo M, Barroso A, Domenech M, Cortes J, et al. Prevalence of BRCA1 and BRCA2 Jewish mutations in Spanish breast cancer patients. Br J Cancer 1999;79:1302–3.[CrossRef][ISI][Medline]cancerlit;99196411
57
FitzGerald MG, MacDonald DJ, Krainer M, Hoover I, O'Neil E, Unsal H, et al. Germ-line BRCA1 mutations in Jewish and non-Jewish women with early-onset breast cancer. N Engl J Med 1996;334:143–9.
58 Offit K, Gilewski T, McGuire P, Schluger A, Hampel H, Brown K, et al. Germline BRCA1 185delAG mutations in Jewish women with breast cancer. Lancet 1996;347:1643–5.[CrossRef][ISI][Medline]cancerlit;96238765
59 Wagner TM, Moslinger RA, Muhr D, Langbauer G, Hirtenlehner K, Concin H, et al. BRCA1-related breast cancer in Austrian breast and ovarian cancer families: specific BRCA1 mutations and pathological characteristics. Int J Cancer 1998;77:354–60.[CrossRef][ISI][Medline]cancerlit;98326728
60 Mullen P, Miller WR, Mackay J, Fitzpatrick DR, Langdon SP, Warner JP. BRCA1 5382insC mutation in sporadic and familial breast and ovarian carcinoma in Scotland. Br J Cancer 1997;75:1377–80.[ISI][Medline]cancerlit;97299913
61 Szabo CI, King MC. Population genetics of BRCA1 and BRCA2 [editorial]. Am J Hum Genet 1997;60:1013–20.[ISI][Medline]cancerlit;97294392
62 Peelen T, van Vliet M, Petrij-Bosch A, Mieremet R, Szabo C, van den Ouweland AM, et al. A high proportion of novel mutations in BRCA1 with strong founder effects among Dutch and Belgian hereditary breast and ovarian cancer families. Am J Hum Genet 1997;60:1041–9.[ISI][Medline]cancerlit;97294395
63 Dorum A, Moller P, Kamsteeg EJ, Scheffer H, Burton M, Heimdal KR, et al. A BRCA1 founder mutation, identified with haplotype analysis, allowing genotype/phenotype determination and predictive testing. Eur J Cancer 1997;33:2390–2.cancerlit;98279243
64 Andersen TI, Borresen AL, Moller P. A common BRCA1 mutation in Norwegian breast and ovarian cancer families? [letter]. Am J Hum Genet 1996;59:486–7.[ISI][Medline]cancerlit;96335726
65 Liede A, Rehal P, Vesprini D, Jack E, Abrahamson J, Narod SA. A breast cancer patient of Scottish descent with germ-line mutations in BRCA1 and BRCA2 [letter]. Am J Hum Genet 1998;62:1543–4.[CrossRef][ISI][Medline]cancerlit;98254478
66 Liede A, Cohen B, Black D, Davidson R, Renwick A, Hoodfar E, et al. Evidence of a founder mutation in Scotland [abstract]. Am J Hum Genet 1999;65:A135.
67 Petrij-Bosch A, Peelen T, van Vliet M, van Eijk R, Olmer R, Drusedau M, et al. BRCA1 genomic deletions are major founder mutations in Dutch breast cancer patients [published erratum appears in Nat Genet 1997;17:503]. Nat Genet 1997;17:341–5.[CrossRef][ISI][Medline]cancerlit;98016423
68
Puget N, Stoppa-Lyonnet D, Sinilnikova OM, Pages S, Lynch HT, Lenoir GM, et al. Screening for germ-line rearrangements and regulatory mutations in BRCA1 led to the identification of four new deletions. Cancer Res 1999;59:455–61.
69 Puget N, Sinilnikova OM, Stoppa-Lyonnet D, Audoynaud C, Pages S, Lynch HT, et al. An Alu-mediated 6-kb duplication in the BRCA1 gene: a new founder mutation? Am J Hum Genet 1999;64:300–2.[CrossRef][ISI][Medline]
70 Smith SA, Easton DF, Evans DG, Ponder BA. Allele losses in the region 17q12–21 in familial breast and ovarian cancer involve the wild-type chromosome. Nat Genet 1992;2:128–31.[CrossRef][ISI][Medline]cancerlit;93265136
71 Chamberlain JS, Boehnke M, Frank TS, Kiousis S, Xu J, Guo SW, et al. BRCA1 maps proximal to D17S579 on chromosome 17q21 by genetic analysis. Am J Hum Genet 1993;52:792–8.[ISI][Medline]cancerlit;93212741
72
Scully R, Anderson SF, Chao DM, Wei W, Ye L, Young RA, et al. BRCA1 is a component of the RNA polymerase II holoenzyme. Proc Natl Acad Sci U S A 1997;94:5605–10.
73 Anderson SF, Schlegel BP, Nakajima T, Wolpin ES, Parvin JD. BRCA1 protein is linked to the RNA polymerase II holoenzyme complex via RNA helicase A. Nat Genet 1998;19:254–6.[CrossRef][ISI][Medline]cancerlit;98324774
74 Scully R, Chen J, Plug A, Xiao Y, Weaver D, Feunteun J, et al. Association of BRCA1 with Rad51 in mitotic and meiotic cells. Cell 1997;88:265–75.[CrossRef][ISI][Medline]cancerlit;97160847
75 Chen JJ, Silver D, Cantor S, Livingston DM, Scully R. BRCA1, BRCA2, and Rad51 operate in a common DNA damage response pathway. Cancer Res 1999;59(7 Suppl):1752s–1756s.
76
Hsu LC, White RL. BRCA1 is associated with the centrosome during mitosis. Proc Natl Acad Sci U S A 1998;95:12983–8.
77 Xu X, Weaver Z, Linke SP, Li C, Gotay J, Wang XW, et al. Centrosome amplification and a defective G2-M cell cycle checkpoint induce genetic instability in BRCA1 exon 11 isoform-deficient cells. Mol Cell 1999;3:389–95.[CrossRef][ISI][Medline]cancerlit;99214854
78
Bailly E, Pines J, Hunter T, Bornens M. Cytoplasmic accumulation of cyclin B1 in human cells: association with a detergent-resistant compartment and with the centrosome. J Cell Sci 1992;101:529–45.
79 Bailly E, Doree M, Nurse P, Bornens M. p34cdc2 is located in both nucleus and cytoplasm; part is centrosomally associated at G2/M and enters vesicles at anaphase. EMBO J 1989;8:3985–95.[ISI][Medline]cancerlit;90076118
80
Pockwinse SM, Krockmalnic G, Doxsey SJ, Nickerson J, Lian JB, van Wijnen AJ, et al. Cell cycle independent interaction of CDC2 with the centrosome, which is associated with the nuclear matrix-intermediate filament scaffold. Proc Natl Acad Sci U S A 1997;94:3022–7.
81 Brown CR, Doxsey SJ, White E, Welch WJ. Both viral (adenovirus E1B) and cellular (hsp 70, p53) components interact with centrosomes. J Cell Physiol 1994;160:47–60.[CrossRef][ISI][Medline]cancerlit;94292559
82 Fukasawa K, Choi T, Kuriyama R, Rulong S, Vande Woude GF. Abnormal centrosome amplification in the absence of p53. Science 1996;271:1744–7.[Abstract]cancerlit;96179680
83 Carroll PE, Okuda M, Horn HF, Biddinger P, Stambrook PJ, Gleich LL, et al. Centrosome hyperamplification in human cancer: chromosome instability induced by p53 mutation and/or Mdm2 overexpression. Oncogene 1999;18:1935–44.[CrossRef][ISI][Medline]cancerlit;99223096
84 Shao N, Chai YL, Shyam E, Reddy P, Rao VN. Induction of apoptosis by the tumor suppressor protein BRCA1. Oncogene 1996;13:1–7.